U.S. patent number 8,821,935 [Application Number 11/583,940] was granted by the patent office on 2014-09-02 for microcapsules with modified release of active principles with low solubility for oral delivery.
This patent grant is currently assigned to Flamel Technologies. The grantee listed for this patent is Catherine Castan, Florence Guimberteau, Remi Meyruiex, Gerard Soula. Invention is credited to Catherine Castan, Florence Guimberteau, Remi Meyruiex, Gerard Soula.
United States Patent |
8,821,935 |
Guimberteau , et
al. |
September 2, 2014 |
Microcapsules with modified release of active principles with low
solubility for oral delivery
Abstract
The present invention is directed to microcapsules for reliably
modified release and adapted to industrial reproduction of an
active principle hardly water-soluble, other than
anti-hyperglycemia agents. Each of said microcapsules comprises a
core of hardly soluble active principle and a coating film applied
on the core. Their mean diameter is less than 1000 microns. The
coating film contains a film-forming polymer (PI) insoluble in
gastrointestinal tract fluids, a water-soluble polymer (P2), a
plasticizer (PL), and optionally a lubricating surfactant (TA).
Said coating film represents at least 4% p/p of dry matter of their
total weight, and its components P1, P2, PL satisfy the following
characteristics: dry weight mass fraction of PI relative to the
total coating weight ranging between 40 and 90%; dry matter weight
fraction of PL/P1+P2 ranging between 15 and 60%; dry matter weight
fraction of PL/P1+P2 ranging between 1 and 30%. The present
invention is also directed to the uses of said microcapsules in
galenic formulation.
Inventors: |
Guimberteau; Florence
(Montussan, FR), Castan; Catherine (Orlienas,
FR), Meyruiex; Remi (Lyons, FR), Soula;
Gerard (Meyzieu, FR) |
Applicant: |
Name |
City |
State |
Country |
Type |
Guimberteau; Florence
Castan; Catherine
Meyruiex; Remi
Soula; Gerard |
Montussan
Orlienas
Lyons
Meyzieu |
N/A
N/A
N/A
N/A |
FR
FR
FR
FR |
|
|
Assignee: |
Flamel Technologies
(Venissieux, FR)
|
Family
ID: |
30011527 |
Appl.
No.: |
11/583,940 |
Filed: |
October 20, 2006 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20070160678 A1 |
Jul 12, 2007 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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11358047 |
Feb 22, 2006 |
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10522234 |
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PCT/FR03/02384 |
Jul 28, 2003 |
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Current U.S.
Class: |
424/489; 424/498;
424/494; 424/497; 424/490 |
Current CPC
Class: |
A61K
9/5026 (20130101); A61K 9/5015 (20130101); A61K
9/5047 (20130101) |
Current International
Class: |
A61K
9/14 (20060101); A61K 9/16 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0207041 |
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Dec 1986 |
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EP |
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0 249 587 |
|
Dec 1987 |
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EP |
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0709087 |
|
May 1996 |
|
EP |
|
0 953 359 |
|
Nov 1999 |
|
EP |
|
2313915 |
|
Jan 1977 |
|
FR |
|
2670112 |
|
Jun 1992 |
|
FR |
|
2 816 840 |
|
May 2002 |
|
FR |
|
2 202 143 |
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Sep 1988 |
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GB |
|
62240618 |
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Oct 1987 |
|
JP |
|
7252140 |
|
Oct 1995 |
|
JP |
|
08073345 |
|
Mar 1996 |
|
JP |
|
10509427 |
|
Sep 1998 |
|
JP |
|
WO-9611675 |
|
Apr 1996 |
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WO |
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WO-99/17752 |
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Apr 1999 |
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WO |
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WO-9949846 |
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Oct 1999 |
|
WO |
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WO-0018374 |
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Apr 2000 |
|
WO |
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WO-00/38686 |
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Jul 2000 |
|
WO |
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WO-02/39984 |
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May 2002 |
|
WO |
|
WO-02/094285 |
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Nov 2002 |
|
WO |
|
Other References
Dubernet, C. and Benoit, J.P., La microencapsulation: ses
techniques et ses applications en biologie, L'actualite chimique,
pp. 19-28, Dec. 1986. cited by applicant.
|
Primary Examiner: Hartley; Michael G
Assistant Examiner: Ebrahim; Nabila
Attorney, Agent or Firm: Squire Patton Boggs (US) LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Ser. No. 11/358,047, filed
Feb. 22, 2006, still pending, which is a continuation of U.S. Ser.
No. 10/522,234, filed Jun. 9, 2006, abandoned, which is a national
stage application of PCT/FR03/002384, filed Jul. 28, 2003, which
claims priority to FR 02/09530, filed Jul. 26, 2002. The contents
of which are incorporated herein in their entirety.
Claims
The invention claimed is:
1. A microcapsule for the modified release of at least one active
principle with low water solubility, wherein the microcapsule
comprises a core comprising at least one active principle, wherein
at least one of the at least one active principle has low
solubility, and a coating film applied onto the core, wherein the
mean diameter of the microcapsule is less than 1000 microns,
wherein the coating film is at least 3% dry weight to total weight,
and comprises: I. at least one film-forming polymer selected from
the group consisting of: acrylic derivatives, poly (vinyl acetate),
water-insoluble derivatives of cellulose, and mixtures thereof,
wherein the polymer is insoluble in gastrointestinal tract fluid;
II. at least one water-soluble polymer selected from the group
consisting of: water-soluble derivatives of cellulose, polyvinyl
alcohols (PVAs), polyoxyethylenes (POEs), polyvinylpyrrolidones
(PVPs), and mixtures thereof; and III. at least one plasticizer,
wherein the at least one film-forming polymer insoluble in
gastrointestinal tract fluid is between 50-80% dry weight relative
to the total mass of the coating; wherein the mass fraction of the
at least one water-soluble polymer dry weight, relative to the
total dry weight of the at least one film-forming polymer insoluble
in gastrointestinal tract fluids and of the at least one
water-soluble polymer, is between 15 and 60%; and wherein the mass
fraction of the at least one plasticizer dry weight, relative to
the total dry weight of the at least one film-forming polymer
insoluble in gastrointestinal tract fluids and the at least one
plasticizer, is between 1 and 30%; wherein the coating film does
not comprise the following combination of components: at least one
film-forming polymer insoluble in gastrointestinal tract fluid,
present in a proportion of 50 to 90% by weight on a dry basis
relative to the total mass of the coating composition, and
consisting of water-insoluble derivatives of cellulose; at least
one nitrogenous polymer, present in a proportion of 2 to 25% by
weight on a dry basis relative to the total mass of the coating
composition, and consisting of; polyacrylamide, poly-N-vinyl-amide,
poly-(N-vinyllactam), and mixtures thereof; at least one
plasticizer, present in a proportion of 2 to 20% by weight on a dry
basis relative to the total mass of the coating composition, and
consisting of: glyceryl esters, phthalates, citrates, sebacates,
cetyl alcohol esters, castor oil, salicylic acid, cutin, and
mixtures thereof; and at least one surfactant or lubricant, present
in a proportion of 2 to 20% by weight on a dry basis relative to
the total mass of the coating composition, and consisting of:
anionic surfactants, nonionic surfactants, lubricants, and mixtures
thereof.
2. The microcapsule of claim 1, wherein the at least one
plasticizer is selected from the group comprising: glycerol and
esters thereof, acetylated glycerides, glyceryl monostearate,
glyceryl triacetate, glyceryl tributyrate, phthalates, dibutyl
phthalate, diethyl phthalate, dimethyl phthalate, dioctyl
phthalate, citrates, acetyl tributyl citrate, acetyl triethyl
citrate, tributyl citrate, triethyl citrate, sebacates, diethyl
sebacate, dibutyl sebacate, adipates, azelates, benzoates, plant
oils, fumarates, diethyl fumarate, malates, diethyl malate,
oxalates, diethyl oxalate, succinates, dibutyl succinate,
butyrates, acetyl alcohol esters, salicylic acid, malonates,
diethyl malonate, castor oil, and mixtures thereof.
3. The microcapsule of claim 1, wherein the coating film also
comprises IV. at least one lubricating surfactant.
4. The microcapsule of claim 3, wherein the at least one
lubricating surfactant is in a proportion of 2 to 20% of the total
mass of the dry coating.
5. The microcapsule of claim 3, wherein the at least one
lubricating surfactant is selected from the group comprising:
anionic surfactants, alkali metal salts of fatty acids,
alkaline-earth metal salts of fatty acids, stearic acid, oleic
acid, polyoxyethylene oils, polyoxyethylenated hydrogenated castor
oil, polyoxyethylene-polyoxypropylene copolymers,
polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil
derivatives, stearates, calcium stearate, magnesium stearate,
aluminum stearate, zinc stearate, stearyl fumarates, sodium stearyl
fumarate, glyceryl behenate, and mixtures thereof.
6. The microcapsule of claim 1, wherein the microcapsule mean
diameter is between 800 and 50 microns.
7. The microcapsule of claim 6, wherein the microcapsule mean
diameter is between 600 and 100 microns.
8. The microcapsule of claim 1, wherein the active principle is
selected from the group comprising: antiulcer agents, antidiabetic
agents, anticoagulants, antithrombics, blood lipid-lowering agents,
antiarrhythmics, vasodilators, antiangina agents,
antihypertensives, vasoprotective agents, fertility promoters,
inducers and inhibitors of uterine labor, contraceptives,
antibiotics, antifungal agents, antiviral agents, anticancer
agents, anti-inflammatories, analgesics, antiepileptics,
antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics,
psychostimulants, antimigraine agents, antidepressives,
antitussives, antihistamines and antiallergic agents.
9. The microcapsule of claim 1, wherein the active principle is
selected from the group comprising: prazosine, acyclovir,
nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen,
indomethacine, diclofenac, sulpiride, terfenadine, carbamazepine,
fluoxetine, alprazolam, famotidine, ganciclovir, spironolactone,
acetylsalicyclic acid, quinidine, morphine, amioxicillin,
paracetamol, metoclopramide, verapamil and mixtures thereof.
10. A medicinal product comprising the microcapsules of claim
1.
11. The medicinal product of claim 10, wherein the form of the
medicinal product is selected from the group comprising: tablet,
gelatin capsule, powder, liquid, and an aqueous suspension.
12. A method of controlling the in vivo release of at least one
active principle with a low water solubility by use of orally
administered microcapsules, wherein the microcapsules comprise a
core comprising at least one active principle, wherein at least one
of the at least one active principle has low solubility, and a
coating film applied onto the core, wherein the mean diameter of
the microcapsule is less than 1000 microns, and wherein the coating
film is at least 3% dry weight to total weight, and comprises I. at
least one film-forming polymer selected from the group consisting
of: acrylic derivatives, poly (vinyl acetate), water-insoluble
derivatives of cellulose, and mixtures thereof, wherein the polymer
is insoluble in gastrointestinal tract fluid; II. at least one
water-soluble polymer selected from the group consisting of:
water-soluble derivatives of cellulose, polyvinyl alcohols (PVAs),
polyoxyethylenes (POEs), polyvinylpyrrolidones (PVPs), and mixtures
thereof; and III. at least one plasticizer, wherein the at least
one film-forming polymer insoluble in gastrointestinal tract fluid
is between 50-80% dry weight relative to the total mass of the
coating; wherein the mass fraction of the at least one
water-soluble polymer dry weight, relative to the total dry weight
of the at least one film-forming polymer insoluble in
gastrointestinal tract fluids and in the at least one water-soluble
polymer, is between 15 and 60%; and wherein the mass fraction of
the at least one plasticizer dry weight, relative to the total dry
weight of the at least one film-forming polymer insoluble in
gastrointestinal tract fluids and the at least one plasticizer, is
between 1 and 30%; wherein the coating film does not comprise the
following combination of components: at least one film-forming
polymer insoluble in gastrointestinal tract fluid, present in a
proportion of 50 to 90% by weight on a dry basis relative to the
total mass of the coating composition, and consisting of
water-insoluble derivatives of cellulose; at least one nitrogenous
polymer, present in a proportion of 2 to 25% by weight on a dry
basis relative to the total mass of the coating composition, and
consisting of; polyacrylamide, poly-N-vinyl-amide,
poly-(N-vinyllactam), and mixtures thereof; at least one
plasticizer, present in a proportion of 2 to 20% by weight on a dry
basis relative to the total mass of the coating composition, and
consisting of: glyceryl esters, phthalates, citrates, sebacates,
cetyl alcohol esters, castor oil, salicylic acid, cutin, and
mixtures thereof; and at least one surfactant or lubricant, present
in a proportion of 2 to 20% by weight on a dry basis relative to
the total mass of the coating composition, and consisting of:
anionic surfactants, nonionic surfactants, lubricants, and mixtures
thereof.
13. The method of claim 12, wherein the coating film also comprises
at least one lubricating surfactant.
14. The microcapsule of claim 1, wherein the at least one active
principle has a water solubility less than 10 g/l.
15. The microcapsule of claim 1, wherein the microcapsules provide
a prolonged or delayed release profile such that the half-release
time t.sub.1/2 is between approximately 0.25 and approximately 20
hours.
Description
The field of the present invention is that of systems with modified
release of medicinal and/or nutritional active principles (APs),
intended to be administered orally.
The present invention also relates to microcapsules intended to be
administered per os and containing at least one AP with low
solubility.
The invention also relates to the medicinal products containing
these microcapsules mentioned above and to the use of the latter
for producing medicinal products.
In the present disclosure, the expression "modified release"
denotes without distinction a release of the active principle(s)
beginning as soon as the pharmaceutical form has been brought into
contact with its dissolving medium (in vivo or in vitro) or else a
release of the active principle(s) beginning only after a
predetermined period of time ranging, for example, from 0.5 to
several hours. Thus, for the purpose of the invention, a prolonging
of the release corresponds to a release time for 50% of the active
principle(s) which is typically several hours and which can extend
from 0.25 to 20 hours, for example.
The expression "low solubility" relates to active principles the
water-solubility of which is less than 10 g/l at 25.degree. C.
More precisely, the invention relates to pharmaceutical
formulations with prolonged release of active principles with low
solubility, this formulation consisting of a plurality of
microcapsules consisting of a core containing the active principle
of low solubility and coated with a layer of polymer which controls
the release of the AP.
Among the various modified-release systems, pharmaceutical systems
with modified release consisting of a plurality of microcapsules of
the reservoir type with an average diameter of less than 1000
microns are particularly advantageous. In fact, in these systems,
the dose of active principle(s) to be administered is distributed
among a large number of microcapsules (typically 10 000 for a dose
of 500 mg and a diameter of 400 microns) and this type of system,
as a result, has the following intrinsic advantages: the use of a
mixture of microcapsules having different modified-release profiles
makes it possible to produce release profiles exhibiting several
waves of release or providing, by means of appropriate regulation
of the various fractions, a constant plasma concentration level of
the AP; the sensitivity to the variability of gastric emptying is
lower, since the emptying, which takes place here with respect to a
large number of particles, is statistically more reproducible;
contact of the tissues with a high dose of AP, "dose dumping", is
avoided. Each microcapsule in fact contains only a very low dose of
active principle (s). The risk of tissue deterioration through
local overconcentration of aggressive active principle(s) is thus
avoided; it is possible to combine several pharmaceutical forms
(immediate and/or delayed and/or prolonged release) comprising one
or more active principles, in these "multimicrocapsular" systems;
it does not induce any degradation of the AP; the amount of time
spent by the microcapsules in the upper parts of the tract can be
prolonged, which ensures an increase in the amount of time spent by
the active principle(s) in passing in front of the absorption
windows and thus maximizes the bioavailability of the active
principle(s).
However, when the solubility of the AP is low, the production of a
microparticulate modified-release form comes up against a
substantial difficulty.
The diffusion of the active principle through the coating film
surrounding each microcapsule takes place under the action of the
dissolved AP concentration gradient between the inside and the
outside of the microcapsule. In other words, it is the difference
in osmotic pressure of the AP between the inside and the outside of
the microcapsule which drives the release. The internal
concentration of AP is the saturation concentration. The external
concentration of AP is, for its part, negligible under usual
conditions (termed "sink"). The driving of release is therefore
directly linked to the saturation concentration of the AP, i.e. to
its solubility.
For APs with low solubility, the saturation concentration of AP is
relatively low and the diffusion of the AP to the outside is
therefore, a priori, very slow, even for coating films that are not
very thick.
Furthermore, in any case, for thin coating films, the following
difficulties are then encountered: (a) The depositing of a very
thin coating film is not even: there are gaps next to areas that
are too thick, and the release of the AP is not prolonged. (b) The
industrial control of the process for a very thin deposit becomes
very difficult and relatively unreproducible.
Moreover, for thicker coating films, the release of the AP is
extremely slow, or even nonexistent.
This technical problem is all the more difficult to solve in that
it must not be down to the detriment of the other specifications
required for a pharmaceutical system for oral administration of AP,
which are, inter alia, cumulatively and for a wide range of APs, as
follows: slow transit in the upper parts of the gastrointestinal
tract, reflected by an in vivo absorption profile which is over a
period of time notably longer than that permitted by the natural
transit (3 h+/-1), absence of irritation of the mucosa, limited
mass of the pharmaceutical form corresponding to a dose, low cost
price.
The difficulty in modifying the release of an AP with low
solubility explains the small number of technical solutions which
have been proposed to date.
As regards the solid, multimicrocapsular pharmaceutical systems,
those consisting of a multiplicity of particles or microcapsules
each carrying active principle(s) coated with a film-coating layer
based on ethylcellulose, on polyvinylpyrrolidone, on magnesium
stearate and on castor oil, for example, are known. Such a
pharmaceutical system is disclosed in PCT application WO 96/11675.
These microcapsule reservoirs obtain an advantage from their
multiplicity, which is a more even and reproducible gastric
emptying time. In addition, their size is between 50 and 1000 .mu.m
and also the characteristics of their coating make it possible to
increase their transit time in the upper parts of the
gastrointestinal tract and, consequently, to maintain absorption of
the active principle(s) for all or part of this time spent in the
small intestine.
However, the multimicrocapsular pharmaceutical system according to
WO 96/11675 is perfectable as regards APs with low solubility that
can be administered orally, since it does not propose any solution
to the problem of the diffusion of such an AP with low solubility
through a coating film of sufficiently large thickness, for example
of several microns.
In the field of microcapsules with modified release of blood
glucose-lowering active principles, mention should be made of
French patent application FR-A-2 816 840 which discloses
microcapsules in which the core consists of metformin crystals
coated with a membrane for controlling the release of the
metformin, comprising stearic acid (50%) or castor oil (10%) and
ethylcellulose (respectively 50 and 90%). This pharmaceutical
system, for the oral administration of blood glucose-lowering
active principles, should make it possible to obtain an effective
therapeutic coverage over 24 hours by overcoming the problems of
by-pass of the absorption window and of massive localized release
of active principle.
This technical problem remains perfectible, insofar as it does not
solve the problem of the low-solubility APs mentioned above.
As regards the prior art on microcapsules with modified release of
active principles with low solubility, mention should first of all
be made of PCT patent application WO 99/49846 which describes a
pharmaceutical preparation composed of submicronic (0.05 to 10
.mu.m) particles combining an active principle with low solubility
with a phospholipid compound, a surface charge-modifying compound
and a block polymer. The aim of this preparation is to improve the
bioavailability and the stability of the active principle and it
finds its applications in injectable forms or alternatively in
forms intended to be administered ocularly or nasally. A
prolonged-release form is only obtained in the case of
intramuscular injection.
PCT patent application WO 00/18374 describes an invention of the
same type as the previous one: the active principle in the form of
submicronic (<1000 nm) particles is stabilized by a compound
associated at the surface of the particles and mixed with a
polymer. This mixture can then be formulated into granules or
pellets and, optionally, into tablets. The active principle is
rapidly dissolved and it is the increase in bioavailability
obtained by virtue of the decrease in size which makes it possible
to have an effective plasma concentration over a prolonged
period.
Patent application GB-2 202 143 describes spheroids of diameter
greater than 0.5 mm, and preferably greater than 0.8 mm, containing
the poorly soluble active principle dispersed in 70 to 99.5% of
microcrystalline cellulose. This matricial form requires no coating
controlling the release of the active principle.
Patent application. JP-8073345 describes a controlled-release
system composed of a film-coated granule. The granule contains an
active principle with low solubility at neutral pH and inorganic
acids. This system therefore proposes a solution that is only
suitable for the case of basic active principles with low
solubility.
Finally, European patent EP-B-0 249 587 concerns a solid
preparation for the slow release of an active substance with low
solubility (<0.1% by weight). This controlled-release
preparation can be provided in the form of gelatin capsules
comprising capsules consisting of coated granules. The granules
comprise the active principle with low solubility and a
solubilizing agent consisting of the commercial product
Cremophor.RTM. RH 40 (polyoxyethylenated hydrogenated castor oil:
40 ethylene oxide units), and also other additives such as
polyvinylpyrrolidone, cellulose, starch and lactose. These granules
of size of between 700 and 1120 .mu.m are covered with an
ethylcellulose coating layer for controlling release. The
ingredients of the granules, namely polyvinylpyrrolidone,
cellulose, cornstarch and lactose, appear to be the elements of the
hydrophilic gel system specific to the pharmaceutical form
according to EP-B-0 24.9 587. These capsules therefore comprise a
single constituent (ethylcellulose) in their coating layer, which
limits its capacities in terms of modification of the release of
the active principle. In particular, it is doubtful whether a
coating layer composed only of ethylcellulose (known to form
impermeable films) would allow the release of an AP with low
solubility in a controlled and industrially reproducible manner
over a period of several hours, for example.
None of these patent applications describes microparticles of the
reservoir type or microcapsules for which the prolonged release of
the active principle with low solubility is controlled by means of
its diffusion through a membrane that is sufficiently thick to
ensure a controlled and industrially reproducible permeability.
Neither do they teach the manner in which such a system can be
successfully achieved.
In the face of this vacuity of the prior art, one of the essential
objectives of the present invention is to propose a form with
modified release of AP(s) with low solubility consisting of a
plurality of microcapsules, each formed by a core containing the AP
and coated with a coating film.
Another objective of the present invention is to provide a
plurality of reservoir-type microcapsules of AP of low solubility,
for oral administration of the latter, the coating film of these
microcapsules being sufficiently thick to ensure a controlled and
industrially reproducible permeability.
Another essential objective of the present invention is to provide
a plurality of microcapsules of AP(s) with low solubility, less
than 1000 .mu.m in size.
Another objective of the present invention is to propose an oral
pharmaceutical form consisting of a large number (for example of
the order of several thousand) of microcapsules, this multiplicity
ensuring, statistically, good reproducibility of the kinetics of
transit of the AP in the entire gastrointestinal tract, such that
better control of the bioavailability and therefore better
effectiveness result therefrom.
Another essential objective of the present invention is to provide
a plurality of microcapsules of AP(s) with low solubility, for oral
administration of the latter according to a prolonged and/or
optionally delayed release profile, such that the half-release
time, t.sub.1/2, is between 0.25 and 20 hours.
Another essential objective of the present invention is to provide
an oral form with modified release in which the AP(s) is (are) in
the form of a plurality of particles individually coated to form
microcapsules, and in which it is possible to mix several active
principles in multimicrocapsular form, that are released according
to different respective release times.
Having set themselves all the above objectives among others, the
inventors have, to their credit, developed a multimicrocapsular
pharmaceutical system with prolonged release of AP(s) with low
solubility, by oral administration, which, besides the properties
targeted in the aims above, has, cumulatively and for a wide range
of APs, the following specifications, inter alia: absence of
irritation of the mucosa, high AP content, low cost price, which
makes it possible to adjust the AP half-release time to between
0.25 and 20 hours, which is reproducible and easy to implement
industrially by virtue of a ratio of the mass of the coating film
to the mass of the particle of greater than 3% dry weight/dry
weight, preferably greater than 5% dry weight/dry weight, and even
more preferably of between 3 and 40% dry weight/dry weight.
To do this, the inventors have, to their credit, discovered, after
many trials, microcapsules with a particular structure which maker
it possible to satisfy the objectives recalled above, among
others.
To this end, a subject of the present invention a pharmaceutical
system made up of microcapsules for the modified release of at
least one AP with low water solubility, with the possible exclusion
of blood glucose-lowering agents, intended to be administered
orally and of the type of those: each consisting of a core
comprising at least one active principle and of a coating film
applied onto the core and controlling the prolonged release of the
AP(s), the mean diameter of which is less than 1000 microns,
preferably between 800 and 50 microns, and even more preferably
between 600 and 100 microns, in which the coating film of each
microcapsule contains the following components: -I--at least one
film-forming polymer (P1) insoluble in gastrointestinal tract
fluids, -II--at least one water-soluble polymer (P2) -III--at least
one plasticizer (PL), -IV--and, optionally, at least one
lubricating surfactant (TA); with the possible exclusion of coating
films consisting of enteric compositions and of coating films
having the composition below: 1--at least one film-forming polymer
(P1) insoluble in the fluids of the tract, present in a proportion
of 50 to 90, preferably 50 to 80% by weight on a dry basis relative
to the total mass of the coating composition and consisting of at
least one water-insoluble derivative of cellulose, i.e.
ethylcellulose and/or cellulose acetate; 2--at least one
nitrogenous polymer (P2) present in a proportion of 2 to 25,
preferably 5 to 15% by weight on a dry basis relative to the total
mass of the coating composition and consisting of at least one
polyacrylamide and/or one poly-N-vinyl-amide and/or one
poly-(N-vinyl lactam), i.e. polyacrylamide and/or
polyvinylpyrrolidone; 3--at least one plasticizer present in a
proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis
relative to the total mass of the coating composition and
consisting of at least one of the following compounds: glyceryl
esters, phthalates, citrates, sebacates, cetyl alcohol esters,
castor oil, salicylic acid and cutin; 4--and at least one
surfactant and/or lubricant, present in a proportion of 2 to 20,
preferably 4 to 15% by weight on a dry basis relative to the total
mass of the coating composition and chosen from anionic
surfactants, i.e. alkali metal salts or alkaline-earth metal salts
of fatty acids, stearic acid and/or oleic acid being preferred,
and/or from nonionic surfactants, i.e. polyoxy-ethylenated sorbitan
esters and/or polyoxy-ethylenated castor oil derivatives, and/or
from lubricants such as calcium stearate, magnesium stearate,
aluminum stearate or zinc stearate, or such as sodium stearyl
fumarate and/or glyceryl behenate; it being possible for said agent
to comprise just one or a mixture of the abovementioned products;
characterized: in that their coating film represents at least 3%
dry weight/dry weight, preferably at least 5% dry weight/dry weight
of their total mass, and in that the components P1, P2 and PL of
the coating film satisfy the following characteristics: mass
fraction by dry weight of P1 relative to the total mass of the
coating of between 40 and 90%, and preferably of between 50 and
80%; mass fraction by dry weight P2/P1+P2 of between 15 and 60%,
and preferably of between 15 and 55%; mass fraction by dry weight
PL/P1+PL of between 1 and 30%, and preferably of between 5 and
25%.
To the applicant's credit, it has developed, entirely surprisingly
and unexpectedly, such a pharmaceutical system that allows
diffusion of the AP with low solubility through a sufficiently
thick coating film for the microcapsules, and without putting a
strain on the cost price.
The choice of an amount of coating greater than or equal to 3% by
weight on a dry basis relative to the total mass of the
microcapsule is a particularly inventive provision which goes
against the technical opinion commonly held in this field. The same
is true as regards the quantitative data for P1, P2 and PL.
According to a particularly preferred embodiment of the invention,
the coating film represents 3 to 40% w/w on a dry basis of the
total mass of the microcapsules.
Preferably, P1 is selected from the group of products below:
water-insoluble derivatives of cellulose, preferably ethylcellulose
and/or cellulose acetate, acrylic derivatives, poly(vinyl
acetates), and mixtures thereof.
Preferably, P2 is selected from the group of products below:
water-soluble derivatives of cellulose, polyacrylamides,
poly-N-vinylamides, poly(N-vinyl lactams), polyvinyl alcohols
(PVAs), polyoxyethylenes (POEs), polyvinylpyrrolidones (PVPs) (the
latter being preferred), and mixtures thereof.
Preferably, PL is selected from the group of products below:
glycerol and esters thereof, preferably from the following
subgroup: acetylated glycerides, glyceryl mono-stearate, glyceryl
triacetate, glyceryl tributyrate, phthalates, preferably from the
following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl
phthalate, dioctyl phthalate, citrates, preferably from the
following subgroup: acetyl tributyl citrate, acetyl triethyl
citrate, tributyl citrate, triethyl citrate, sebacates, preferably
from the following subgroup: diethyl sebacate, dibutyl sebacate,
adipates, azelates, benzoates, plant oils, fumarates, preferably
diethyl fumarate, malates, preferably diethyl malate, oxalates,
preferably diethyl oxalate, succinates, preferably dibutyl
succinate, butyrates, cetyl alcohol esters, salicylic acid,
triacetin, malonates, preferably diethyl malonate, cutin, castor
oil (this being particularly preferred), and mixtures thereof.
According to an advantageous variant, the coating film comprises
component TA in a proportion of 2 and 20%, and preferably of
between 4 and 15% of the total mass of the dry coating.
Preferably, TA is selected from the group of products below:
anionic surfactants, preferably from the subgroup of alkali metal
salts or alkaline-earth metal salts of fatty acids, stearic acid
and/or oleic acid being preferred, and/or nonionic surfactants,
preferably from the following subgroup: polyoxyethylenated oils,
preferably polyoxyethylenated hydrogenated castor oil,
polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated
sorbitan esters, polyoxyethylenated castor oil derivatives,
stearates, preferably calcium stearate, magnesium stearate,
aluminum stearate or zinc stearate, stearyl fumarates, preferably
sodium stearyl fumarate, glyceryl behenate, and mixtures
thereof.
Advantageously, the microcapsules are designed so as to be able to
spend at least approximately 5 hours, preferably at least
approximately 8 hours, in the upper parts of the gastrointestinal
tract, and thus allow absorption of the AP for a prolonged period
of time.
According to a particular embodiment of the microcapsules
containing APs with low solubility according to the invention, and
according to another quantitative mode of expression, the coating
film comprises from 35 to 75% of ethylcellulose P1, from 20 to 50%
of polyvinylpyrrolidone P2, from 5 to 15% of PL.
This preparation according to the invention makes it possible to
produce a multimicrocapsular form with modified release of APs with
low solubility, it being possible for the AP half-release time to
be adjusted to between 0.25 and 20 hours in a reproducible manner
through the use of a coating film, that can be described as a
diffusion coating film, which is sufficiently thick.
Moreover, for APs with low solubility for which the absorption
window is limited, such a plurality of microcapsules (typically 10
000 for a dose of 500 mg and a mean diameter of 400 microns) has
the following intrinsic advantages: The use of a mixture of
microcapsules having different delayed- and controlled-release
profiles makes it possible to produce release profiles exhibiting
several waves of release or providing, by means of adequate
regulation of the various fractions, a constant plasma
concentration level of the AP. The variability of gastric emptying
is lower, since the emptying, which takes place here with respect
to a large number of particles, is statistically more reproducible.
Contact of the tissues with a high dose of AP, "dose dumping", is
avoided. Each microcapsule in fact contains only a very low dose of
AP. The risk of tissue deterioration through a local
overconcentration of aggressive AP is thus avoided. The amount of
time spent by the microcapsules in the upper parts of the tract can
be prolonged, which ensures an increase in the amount of time spent
by the AP in passing in front of the absorption windows and thus
maximizes the bioavailability of the AP.
The APs with low solubility used for preparing the
modified-release, preferably controlled release, microcapsules
according to the invention can be chosen from at least one of the
major varieties of active substances below:
antiulcer agents, antidiabetic agents, anticoagulants,
antithrombics, blood lipid-lowering agents, anti-arrhythmics,
vasodilators, antiangina agents, anti-hypertensives, vasoprotective
agents, fertility promoters, inducers and inhibitors of uterine
labor, contraceptives, antibiotics, antifungal agents, anti-viral
agents, anticancer, agents, anti-inflammatories, analgesics,
antiepileptics, antiparkinsonian agents, neuroleptics, hypnotics,
anxiolytics, psychostimulants, antimigraine agents,
antidepressives, antitussives, antihistamines or antiallergic
agents.
Preferably, the AP(s) is (are) chosen from the following compounds:
prazosine, acyclovir, nifedipine, naproxen, ibuprofen, ketoprofen,
fenoprofen, indomethacine, diclofenac, sulpiride, terfenadine,
carbamazepine, fluoxetine, alprazolam, famotidine, ganciclovir,
spironolactone, acetylsalicyclic acid, quinidine, morphine,
amoxicillin, paracetamol, metoclopramide, verapamil and mixtures
thereof.
According to one variant, the AP consists of at least one
nutritional and/or dietetic supplement, preferably chosen from
vitamins, amino acids, trace elements, antioxidants and mixtures
thereof.
As regards the preparation of the microcapsules according to the
invention, this goes back to micro-encapsulation techniques
accessible to those skilled in the art, the principles of which are
summarized in the article by C. Duverney and J. P. Benoit in
"L'actualite chimique" [Current use in chemistry], December 1986.
More precisely, the technique under consideration is
microencapsulation by film-coating, resulting in individualized
"reservoir" systems as opposed to matricial systems.
For further details, reference will be made to patent EP-B-0.953
359.
The AP particles of desired mean particle size necessary for
preparing the microcapsules according to the invention may be
crystals of pure AP and/or AP that has undergone a pretreatment by
one of the conventional techniques in the field, such as for
example granulation, in the presence of at least one conventional
binding agent and/or of an agent for modifying the intrinsic
solubility characteristics of the AP.
The present invention is also directed toward a medicinal product
comprising the microcapsules as defined above.
This medicinal product may be in solid form: tablet, gelatin
capsule, powder, etc, or a in liquid form, for example an aqueous
suspension.
In accordance with the invention, it is also proposed, as a
solution to the problems mentioned at the beginning of the present
disclosure, namely: modified, preferably prolonged, release of APs
with low solubility, in a pharmaceutical form that can be readily
swallowed, all this in a perspective of long, effective and safe
therapeutic coverage,
to use a plurality of microcapsules for the modified release of at
least one AP with low water solubility, with the possible
exclusion: of blood glucose-lowering agents, intended to be
administered orally, these microcapsules having these following
characteristics: they each consist of a core comprising at least
one active principle and of a coating film applied onto the core
and controlling the prolonged release of the AP(s), their mean
diameter is less than 1000 microns, preferably between 800 and 50
microns, and even more preferably between 600 and 100 microns,
their coating film contains the following components: -I--at least
one film-forming polymer (P1) insoluble in gastrointestinal tract
fluids, -II--at least one water-soluble polymer (P2), -III--at
least one plasticizer (PL), -IV--and, optionally, at least one
lubricating surfactant (TA); components P1, P2 and PL of the
coating film satisfying the following characteristics: mass
fraction by dry weight of P1 relative to the total mass of the
coating of between 40 and 90%, preferably of between 50 and 80%;
mass fraction by dry weight of P2/P1+P2 of between 15 and 60%, and
preferably of between 15 and 55%; mass fraction by dry weight
PL/P1+PL of between 1 and 30%, and preferably of between 5 and 25%,
and this coating film represents at least 3% dry weight/dry weight,
preferably at least 5% dry weight/dry weight of their total mass;
with the possible exclusion of coating films consisting of enteric
compositions and of coating films having the composition below:
1--at least one film-forming-polymer (P1) insoluble in the fluids
of the tract, present in a proportion of 50 to 90, preferably 50 to
80% by weight on a dry basis relative to the total mass of the
coating composition and consisting of at least one water-insoluble
derivative of cellulose, i.e. ethylcellulose and/or cellulose
acetate; 2--at least one nitrogenous polymer (P2) present in a
proportion of 2 to 25, preferably 5 to 15% by weight on a dry basis
relative to the total mass of the coating composition and
consisting of at least one polyacrylamide and/or one
poly-N-vinyl-amide and/or one poly(N-vinyl lactam), i.e.
polyacrylamide and/or polyvinylpyrrolidone; 3--at least one
plasticizer present in a proportion of 2 to 20, preferably 4 to 15%
by weight on a dry basis relative to the total mass of the coating
composition and consisting of at least one of the following
compounds: glyceryl esters, phthalates, citrates, sebacates, cetyl
alcohol esters, castor oil, salicylic acid and cutin; 4--and at
least one surfactant and/or lubricant, present in a proportion of 2
to 20, preferably 4 to 15% by weight on a dry basis relative to the
total mass of the coating composition and chosen from anionic
surfactants, i.e. alkali metal salts or alkaline-earth metal salts
of fatty acids, stearic acid and/or oleic acid being preferred,
and/or from nonionic surfactants, i.e. polyoxy-ethylenated sorbitan
esters and/or polyoxy-ethylenated castor oil derivatives, and/or
from lubricants such as calcium stearate, magnesium stearate,
aluminum stearate or zinc stearate, or such as sodium stearyl
fumarate and/or glyceryl behenate; it being possible for said agent
to comprise just one or a mixture of the abovementioned products;
for producing a medicinal product based on at least one AP with low
solubility which can be administered orally, which can be readily
swallowed, and which is released in vivo in a controlled, prolonged
and, optionally, delayed manner.
According to yet another of its objects, the present invention
relates to a method of therapeutic treatment, in which use is made
of a medicinal product as defined above as a product per se or as a
product obtained by means of the method described above.
The invention will be understood more fully, in terms of its
composition and the properties and obtaining thereof, on reading
the examples below, given only by way of illustration and making it
possible to highlight the variants of implementation and the
advantages of the invention.
DESCRIPTION OF THE FIGURES
FIG. 1 represents the curve of the percentage dissolution (% D) of
the active principle AP, as a function of the time (t) in hours
(H), of the microcapsules of example 1, in the dissolving test
described in the following examples.
FIG. 2 represents the curve of the percentage dissolution (% D) of
the active principle AP, as a function of the time (t) in hours
(H), of the microcapsules of example 2, in the dissolving test
described in the following examples.
EXAMPLES
Example 1
Preparation of Acyclovir Microcapsules
Step 1: Granule
970 g of Acyclovir and 30 g of Povidone (Plasdone.RTM. K29/32) are
dry-mixed beforehand in the tank of a high-shear granulator
(Lodige.RTM. M5MRK) for 5 minutes. This pulverulent mixture is then
granulated with water (200 g). The granules are dried at 40.degree.
C. in a ventilated oven, and then sized on a 500 .mu.m screen. The
200-500 .mu.m fraction is selected by sieving.
Step 2: Coating
700 g of granules obtained above are coated, in a Glatt.RTM. GPCG1
fluidized airbed device, with 50.65 g of ethylcellulose
(Ethocel.RTM. 7 Premium), 50.65 g of Povidone (Plasdone.RTM.
K29/32), 12.35 g of magnesium stearate and 9.88 g of castor oil
dissolved in an acetone/isopropanol (60/40 m/m) mixture.
TABLE-US-00001 Microcapsule composition: Production Ingredients %
by mass formula (in g) Acyclovir granules 85.0 700.0 L Plasdone
.RTM. K29/32 (2.55) Acyclovir (82.45) Coating 15.0 123.5 Ethocel
.RTM. 7 Premium (6.15) Plasdone .RTM. K29/32 (6.15) magnesium
stearate (1.50) castor oil (1.20)
Test:
The kinetics of release of the Acyclovir are determined by means of
a dissolving test (type II device according to the European
pharmacopoeia, 3rd edition, phosphate buffer medium, pH 6.8, volume
900 ml, temperature 37.degree. C., 100 rpm paddle agitation, UV
detection at 268 nm).
Result:
The attached FIG. 1 shows the dissolution profile obtained by means
of these microcapsules.
The microcapsule composition described above makes it possible to
obtain a dissolution profile characterized by 80% of Acyclovir
released at 3 hours.
Example 2
Preparation of Amoxicillin Microcapsules
Step 1: Granule
970 g of amoxicillin trihydrate and 30 g of Povidone (Plasdone.RTM.
K29/32) are dry-mixed beforehand in the tank of a high-shear
granulator (Lodige.RTM. M5MRK) for 5 minutes. This pulverulent
mixture is then granulated with water (200 g). The granules are
dried at 40.degree. C. in a ventilated oven and then sized on a 500
.mu.m screen. The 200-500 .mu.m fraction is selected by
sieving.
Step 2: Coating
700 g of granules obtained above are coated, in a Glatt.RTM. GPCG1
fluidized airbed device, with g of ethylcellulose (Ethocel.RTM. 7
Premium), g of Povidone (Plasdone.RTM. K29/32) and 0.96 g of castor
oil dissolved in an acetone/isopropanol (60/40 m/m) mixture.
TABLE-US-00002 Microcapsule composition Production Ingredients % by
mass formula (in g) Amoxicillin granules 82.0 700.0 Plasdone .RTM.
K29/32 (0.45) Amoxicillin trihydrate (14.55) Coating 18.0 153.6
Ethocel .RTM. 7 Premium (12.60) Plasdone .RTM. K29/32 (4.14) Castor
oil (1.26)
Test:
The kinetics of release of the amoxicillin are determined by means
of a dissolving test (type II device according to the European
pharmacopoeia, 3rd edition, phosphate buffer medium, pH 6.8, volume
900 ml, temperature 37.degree. C., 100 rpm paddle agitation, UV
detection at 240 nm).
Result:
The attached FIG. 2 shows the dissolution profile obtained for
these microcapsules.
The microcapsule composition described above makes it possible to
obtain a dissolution profile characterized by 80% of amoxicillin
released at 4 hours.
* * * * *